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dc.contributor.authorLiu, Xin
dc.contributor.authorWang, Ling
dc.contributor.authorZhao, Kehao
dc.contributor.authorThompson, Paul R
dc.contributor.authorHwang, Yousang
dc.contributor.authorMarmorstein, Ronen
dc.contributor.authorCole, Philip A.
dc.date2022-08-11T08:11:00.000
dc.date.accessioned2022-08-23T17:28:22Z
dc.date.available2022-08-23T17:28:22Z
dc.date.issued2008-02-14
dc.date.submitted2015-06-03
dc.identifier.citationNature. 2008 Feb 14;451(7180):846-50. doi: 10.1038/nature06546. <a href="http://dx.doi.org/10.1038/nature06546">Link to article on publisher's site</a>
dc.identifier.issn0028-0836 (Linking)
dc.identifier.doi10.1038/nature06546
dc.identifier.urihttp://hdl.handle.net/20.500.14038/50064
dc.description<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>
dc.description.abstractThe transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/CBP HAT activity contributes to various diseases including cancer. Sequence alignments, enzymology experiments and inhibitor studies on p300/CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/PCAF and MYST HATs. Here we describe a high-resolution X-ray crystal structure of a semi-synthetic heterodimeric p300 HAT domain in complex with a bi-substrate inhibitor, Lys-CoA. This structure shows that p300/CBP is a distant cousin of other structurally characterized HATs, but reveals several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, we propose that p300/CBP uses an unusual 'hit-and-run' (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations can also be readily accounted for by the p300 HAT structure. These studies pave the way for new epigenetic therapies involving modulation of p300/CBP HAT activity.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=18273021&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://dx.doi.org/10.1038/nature06546
dc.subjectAcetylation
dc.subjectAmino Acid Sequence
dc.subjectCatalysis
dc.subjectCrystallography, X-Ray
dc.subjectDimerization
dc.subjectHistone Acetyltransferases
dc.subjectsynthesis
dc.subjectKinetics
dc.subjectModels, Molecular
dc.subjectMolecular Sequence Data
dc.subjectProtein Structure, Tertiary
dc.subjectStructure-Activity Relationship
dc.subjectp300-CBP Transcription Factors
dc.subjectsynthesis
dc.subjectBiochemistry
dc.subjectEnzymes and Coenzymes
dc.subjectMedicinal-Pharmaceutical Chemistry
dc.subjectTherapeutics
dc.titleThe structural basis of protein acetylation by the p300/CBP transcriptional coactivator
dc.typeJournal Article
dc.source.journaltitleNature
dc.source.volume451
dc.source.issue7180
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/thompson/70
dc.identifier.contextkey7172291
html.description.abstract<p>The transcriptional coactivator p300/CBP (CREBBP) is a histone acetyltransferase (HAT) that regulates gene expression by acetylating histones and other transcription factors. Dysregulation of p300/CBP HAT activity contributes to various diseases including cancer. Sequence alignments, enzymology experiments and inhibitor studies on p300/CBP have led to contradictory results about its catalytic mechanism and its structural relation to the Gcn5/PCAF and MYST HATs. Here we describe a high-resolution X-ray crystal structure of a semi-synthetic heterodimeric p300 HAT domain in complex with a bi-substrate inhibitor, Lys-CoA. This structure shows that p300/CBP is a distant cousin of other structurally characterized HATs, but reveals several novel features that explain the broad substrate specificity and preference for nearby basic residues. Based on this structure and accompanying biochemical data, we propose that p300/CBP uses an unusual 'hit-and-run' (Theorell-Chance) catalytic mechanism that is distinct from other characterized HATs. Several disease-associated mutations can also be readily accounted for by the p300 HAT structure. These studies pave the way for new epigenetic therapies involving modulation of p300/CBP HAT activity.</p>
dc.identifier.submissionpaththompson/70
dc.contributor.departmentDepartment of Biochemistry and Molecular Pharmacology
dc.source.pages846-50


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